Project Summary Detection of subclinical malignancy in draining lymph nodes has tremendous importance in the management of a variety of malignancies including esophageal cancer. The tumor status of regional lymph nodes prior to surgery provides important information on which to base both prognosis and therapy. Endoscopic ultrasound (EUS) is increasingly being used in conjunction with cross-sectional imaging for assessing the loco-regional spread of tumor in esophageal cancer patients. However, the accuracy of EUS alone for identification of sentinel lymph nodes has been shown to be poor (40-60%), resulting in improper tumor staging and excessive nodal biopsy. Consequently, it is essential to improve on the modest accuracy rates of EUS imaging in nodal staging, given the important prognostic implications of nodal involvement and the potential impact this may have in selecting patients for therapy. Our group and others have demonstrated that sentinel lymph nodes can be detected with contrast-enhanced ultrasound (CEUS) following intra or peri-tumoral injections of Sonazoid (GE Healthcare), due to uptake of the agent by the reticuloendothelial system (termed lymphosonography). Following injection, migration of the agent can be visualized through the lymphatic channels to the sentinel lymph nodes in real time (generally within 15 minutes of injection). In addition, we have shown an ability to perform contrast-enhanced EUS for the visualization of pancreatic tumor vasculature following intravenous injection of ultrasound contrast agent. Hence, we expect the combination of these two techniques to be both feasible and useful in the identification of sentinel lymph nodes in esophageal cancer patients. The goal of this study is to leverage our previous experiences in contrast-enhanced EUS and lymphosonography to overcome the unmet clinical need of improving the accuracy of EUS-guided node biopsy in esophageal cancer patients. Consenting patients with biopsy proven esophageal cancer will first undergo EUS to identify nodes for biopsy. Following nodal identification by the current clinical standard of care, peri- tumoral injection of Sonazoid will be performed, followed by lymphosonographic detection of sentinel lymph nodes. Subsequently all identified nodes will be biopsied and pathology used as a reference standard. Data from this clinical trial will then be analyzed to determine if lymphosonography improves the specificity, sensitivity, and tumor staging of EUS in esophageal cancer. At the conclusion of this project, we expect to have demonstrated the clear benefits of lymphosonography with EUS in esophageal cancer staging, which will lead to improved clinical decision making and improved patient outcomes.